CN103237544A - Pharmaceutical compositions - Google Patents

Pharmaceutical compositions Download PDF

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Publication number
CN103237544A
CN103237544A CN2011800576307A CN201180057630A CN103237544A CN 103237544 A CN103237544 A CN 103237544A CN 2011800576307 A CN2011800576307 A CN 2011800576307A CN 201180057630 A CN201180057630 A CN 201180057630A CN 103237544 A CN103237544 A CN 103237544A
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Prior art keywords
medical composition
composition
chemical compound
tpgs
vitamin
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Inventor
曹育
W·哈克尔
P·李
李守峰
T·莫扎
H·策恩德纳
朱嘉豪
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Novartis Vaccines and Diagnostics AG
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Novartis Vaccines and Diagnostics AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The present invention relates to a pharmaceutical composition for the oral administration of a therapeutic compound of formula (I), which comprises granules that comprise at least therapeutic compound of formula (I) (see below), particularly 2-Methyl-2-[4-(3-methyl-2-oxo-8- quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile or 8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one, or a tautomer thereof, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof; at least one non-ionic surfactant that is Vitamin E-TPGS in an amount ranging from about 15 to about 80% by weight of the composition; and at least one a dissolution enhancing agent selected from polyethylene glycol, polyethylene oxide, and any combination of the foregoing. The present invention also relates to processes for making such pharmaceutical compositions; a kit comprising such pharmaceutical composition and the instructions provide that the pharmaceutical composition may be taken immediately to about thirty minutes after the consumption of food; and related uses and methods of treatment.

Description

Pharmaceutical composition
Technical field
The present invention relates to a kind of medical composition for the chemical compound for the treatment of shown in the orally give formula (I), this medical composition comprises granule, these granules comprise treats chemical compound (vide infra) shown in the formula (I), it specifically is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2,3-dihydro-imidazol-also [4,5-c] quinoline-1-yl) phenyl]-propionitrile or 8-(6-methoxyl group-pyridin-3-yl)-3-methyl isophthalic acid-(4-piperazine-1-base-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-also [4,5-c] tautomers such as quinoline-2-one-or its, or its etc. medicine acceptable salt or hydrate or solvate; Account at least a nonionic surfactant of about 15 to about 80 weight % amount of said composition, this surfactant is vitamin E-TPGS; And be selected from least a stripping reinforcing agent of Polyethylene Glycol, poly(ethylene oxide) and above person's combination in any.The invention still further relates to the method for making these medical compositions.
Background technology
In normal cell, phosphatidylinositol-3-kinase (PI3K) is the various kinds of cell function regulator of (comprising protein synthesis and glucose metabolism, cell survival and growth, propagation, cellular-restoring and reparation, cell migration and angiogenesis).Conclusive proof, in many tumors, PI3K signal conducting path is the composition activation.(that is, inactivation PTEN) causes composition signal conduction and carcinogenecity through the activation of sudden change or negative regulator in catalysis subelement (PIK3CA) in the PI3K path.The imbalance of be sure oing the PI3K path is one of the most common event of various human cancers (comprise, but be not restricted to, cancer of pancreas and breast carcinoma).
Concrete imidazoquinolie derivative compound shown in the formula (I)
Figure BDA00003273913900011
R wherein 1, R 2, R 3, R 4, R 5, n, R 6And R7 as defined herein, or its tautomer, or its medical acceptable salt or hydrate or solvate are the phosphatidylinositol-3-kinases (PI3K) and mammal rapamycin target protein (mTOR) double inhibitors that can be used for treating various proliferative disorders.These chemical compounds and etc. preparation be disclosed among the WO2006/122806.Prove, these imidazoquinolie derivants, as 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2,3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-propionitrile or 8-(6-methoxyl group-pyridin-3-yl)-3-methyl isophthalic acid-(4-piperazine-1-base-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-also [4,5-c] quinoline-2-one-and etc. medical acceptable salt be effective two PI3K/mTOR inhibitor, for example, WO2006/122806, people such as WO2008/103636 and Maira, Mol.Cancer Ther., 7 (7): 1851-1863 (in July, 2008) has showed multiple extensive activity of cultivating the human cancer cell such as its antagonism such as grade.
Needing will be suc as formula the concrete imidazoquinolie derivative compound shown in (I), it specifically is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2,3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-propionitrile or 8-(6-methoxyl group-pyridin-3-yl)-3-methyl isophthalic acid-(4-piperazine-1-base-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-also [4,5-c] quinoline-2-one-, or its etc. tautomer or medical acceptable salt or hydrate or solvate be mixed with medical composition, specifically be solid oral dosage form, so the treatment benefit of these chemical compounds can be offered the patient of demand.To the challenge that solves this demand be these the treatment chemical compounds physicochemical properties.Formula (I) chemical compound, it specifically is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl]-propionitrile and medical acceptable salt thereof have hypotonicity and strong pH rely on dissolubility (when pH greater than 3 the time, dissolubility is about 0%).These chemical compounds be difficult to preparation and send (that is, when oral absorptions, can be enough being biological utilisation) and be tending towards under under one's belt the acid condition dissolving and subsequently the enteral under condition of neutral pH precipitate.
But one of purpose of the present invention provides the stripping of a kind of improved treatment chemical compound when the patient of demand is arranged and the medical composition of absorption.Another object of the present invention provides the medical composition that is the peroral dosage form that the patient can take in.
Find that unexpectedly medical composition of the present invention surpasses expectedly significantly improves stripping and the absorption of this treatment chemical compound when the patient of demand is arranged.Find that further medical composition of the present invention can be supersaturation with the acidity in intestines and stomach and can be mixed with the peroral dosage form that the object of demand can be taken in safely through preparation when neutral pH is changed.
Summary of the invention
The present invention relates to a kind of for treat shown in the orally give formula (I) chemical compound (as hereinafter the definition) medical composition, this medical composition comprises granule, these granules comprise shown in the formula (I) treats chemical compound; At least a nonionic surfactant of the amount of about 15 to 80 weight % of said composition, this surfactant are vitamin E TPGS; And be selected from least a stripping reinforcing agent of the combination in any of Polyethylene Glycol, poly(ethylene oxide) and above material.This medical composition can optionally further comprise medical acceptable disintegrating agent, adhesive, lubricant, fluidizer, filler, diluent, coloring agent, flavoring agent or antiseptic.
In a preferred embodiments of the present invention, medical composition of the present invention is the supersaturation system.
Treating chemical compound shown in the formula (I), specifically is compd A or compd B, is with about 1 to about 99%, preferable about 30 to about 60%, and even better about 35% to about 60% amount exist.
Vitamin E TPGS be with said composition about 15 to about 80 weight %, for example, about 15 to about 45%, about 15 to about 35% or about amount of 30% to 45% be present in this medical composition.
This stripping reinforcing agent be with said composition about 1 to about 15 weight %, for example, about 1% to about 10%, for example, about 4% to about 8%, for example, about 4% to about 7% amount is present in this medical composition.
The invention further relates to a kind of method of making medical composition of the present invention, this method forms these granules and subsequently these particle formulation is become peroral dosage form by melt pelletization.
The invention further relates to a kind of peroral dosage form that comprises medical composition of the present invention.
The invention further relates to medical composition of the present invention in the purposes for the treatment of proliferative disease.
The invention further relates to medical composition of the present invention in the purposes for the treatment of mTOR kinases dependence disease.
The invention further relates to a kind of medicine box, it comprises the medicinal composition for oral use that (a) comprises granule, and these granules comprise shown in the formula (I) treats chemical compound; At least a nonionic surfactant of the amount of about 15 to the 80 weight % of said composition, this surfactant are vitamin E TPGS; And be selected from least a stripping reinforcing agent of the combination in any of Polyethylene Glycol, poly(ethylene oxide) and above material, reach (b) written explanation, wherein these written explanations are pointed out, take between about 2 hours after these medicinal composition for oral use can extremely be taken food on the feed in preceding 30 minutes.Preferable, these written explanations point out that these medicinal composition for oral use back are on the feed taken in the time of about 30 minutes immediately.
The invention further relates to medical composition of the present invention in the purposes for the treatment of proliferative disease or mTOR kinases dependence disease, this purposes comprises the object that medical composition is had demand with food, this medical composition comprises granule, and these granules comprise shown in the formula (I) treats chemical compound; At least a nonionic surfactant of the amount of about 15 to the 80 weight % of said composition, this surfactant are vitamin E TPGS; And be selected from least a stripping reinforcing agent of the combination in any of Polyethylene Glycol, poly(ethylene oxide) and above material, cause and compare when giving object with this medical composition under the fasting state, the bioavailability that gives this medical composition up-to-date style (I) chemical compound with food increases.
The invention further relates to medical composition of the present invention in the purposes for the treatment of proliferative disease or mTOR kinases dependence disease, this purposes comprises the object that medical composition is had demand with food, this medical composition comprises granule, and these granules comprise shown in the formula (I) treats chemical compound; At least a nonionic surfactant of the amount of about 15 to the 80 weight % of said composition, this surfactant are vitamin E TPGS; And be selected from least a stripping reinforcing agent of the combination in any of Polyethylene Glycol, poly(ethylene oxide) and above material, cause with following food formula (I) not being compared when chemical compound gives object, the bioavailability that gives this medical composition up-to-date style (I) chemical compound with food increases.
The invention further relates to a kind of method for the treatment of proliferative disease or mTOR kinases dependence disease, this method comprises the medical composition of the present invention that will comprise formula (I) chemical compound for the treatment of effective dose has demand with food object, cause comparing when not following food to give object with this medical composition, the bioavailability that gives this medical composition up-to-date style (I) chemical compound with food increases.
The invention further relates to a kind of method for the treatment of proliferative disease or mTOR kinases dependence disease, this method comprises the medical composition of the present invention that will comprise formula (I) chemical compound for the treatment of effective dose has demand with food object, cause with following food formula (I) not being compared when chemical compound gives object, the bioavailability that gives this medical composition up-to-date style (I) chemical compound with food increases.
Brief Description Of Drawings
The accompanying drawing of incorporating into and constituting this description part will show illustrative embodiments of the present invention.
Fig. 1 shows the stripping overview of six kinds of different medical compositions that are capsule formulation.Each capsule with 2:2 than inclusion compound A and nonionic surfactant vitamin E TPGS.In these six kinds of capsules four comprise 25mg, 45mg, 100mg or 50mg PEG3350 in addition, and the capsule that comprises 50mg PEG3350 comprises the 50mg crospovidone in addition.These capsules are placed 900mL 0.1N HCl (pH1.2), utilize USP equipment I I in 100rpm and 37 ℃ of rotations down.This figure shows that the capsule that contains vitamin E TPGS and PEG3350 is faster compared to the suitable capsule stripping that only contains vitamin E TPGS.
Fig. 2 shows the result of 2 steps formula stripping test, carries out this 2 step formula stripping and tests with the stripping overview of single compd A, formulation variants 1 and formulation variants 2 more as described herein.
The capsule that will contain single compd A, formulation variants 1 or variant 2 places 900mL pH2 HCl and stirs 10 to 100 minutes (at about 60 minutes to 90 minutes time stir fast) in the USP equipment I I that rotates subsequently under 50rpm.When about 100 minutes time points, this medium is adjusted to pH6.8 and 1000ml volume and in the USP equipment I I that under 50rpm, rotates, stirs subsequently.Utilizing 100 μ m Varian full flow filters filtered sample to reach analyzes by UV.
Fig. 3 shows that transitivity/advanced solid tumor is suffered from research and by the patient's of 800mg compd A treatment preliminary study result.The patient is by the SDS capsule of preparing according to the present invention or the treatment of SDS medicine bag.These figure show that it is little that the grand mean medicine exposure of SDS medicine bag changes the variation that presents than the SDS capsule.
Detailed Description Of The Invention
The present invention relates to a kind of medical composition for the chemical compound for the treatment of shown in the orally give formula (I), this medical composition comprises granule, and these granules comprise shown in the formula (I) treats chemical compound; At least a nonionic surfactant of the amount of about 15 to the 80 weight % of said composition, this surfactant are vitamin E TPGS; And be selected from least a stripping reinforcing agent of the combination in any of Polyethylene Glycol, poly(ethylene oxide) and above material.This medical composition can optionally further comprise medicine can accept disintegrating agent, adhesive, lubricant, fluidizer, filler, diluent, coloring agent, flavoring agent and antiseptic.
As used herein, term " medical composition " means and gives mammal (for example, the mankind) influences this mammiferous disease specific or the patient's condition with prevention, treatment or control the physical mixture for the treatment of chemical compound that contains.Term " medical composition " for example, also is encompassed in the even physical mixture that forms under high temperature and the high pressure as used herein.
As used herein, term " medicine can be accepted " refers to that suitable tissue with mammal (specifically being human) contacts and do not produce and those chemical compounds, material, compositions and/or the dosage form of reasonable benefit risk than the overdosage toxicity that matches, stimulation, anaphylaxis and other problem complication in correct medical judgment scope.
As used herein, term " treatment chemical compound " means and has any chemical compound, material, medicine, medicament or the active ingredient that treatment or pharmacotoxicological effect and the suitable compositions mode that gives with special suitable for oral administration give mammal (for example, the mankind).In the present invention, useful especially treatment chemical compound is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2,3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-propionitrile and toluene monooxygenase sulfonate (compd A) and 8-(6-methoxyl group-pyridin-3-yl)-3-methyl isophthalic acid-(4-piperazine-1-base-3-trifluoromethyl-phenyl)-1, the 3-dihydro-imidazol-also [4,5-c] quinoline-2-one-(compd B) and etc. medical acceptable salt.
As used herein, term " treatment effective dose " refers to amount or the concentration of the symptom of effective minimizing, elimination, treatment, prevention or the control mammiferous disease of influence or the patient's condition.Term " control " means all methods of slowing down, upset, prevent or stopping the progress of the mammiferous disease of influence or the patient's condition.Yet " control " needn't refer to eliminate fully all diseases and patient's condition symptom.
As used herein, term " is namely released " and (is for example referred to most treatment chemical compound, greater than about 50%, about 60%, about 70%, about 80% or about 90%) (for example, in 100 minutes, 60 minutes, 40 minutes or 30 minutes after oral absorption) release fast in the relative short time.The condition of specifically namely releasing for the TA chemical compound will be known by this area general technology person.
As used herein, term " treatment " comprises preventative (prevention) and therapeutic treatment, and the progress that postpones disease or imbalance.Term " delay progress " means medical composition is in the early stage of proliferative disease to be treated or early stage patient as used herein, in these patients, for example, diagnosed out the tendency of corresponding disease, or these patients are the diseases that are in the disease during (for example) therapeutic treatment or can may develop into corresponding disease because of happenstance.
As used herein, term " gives with food " to refer to, for example, contains any solid or the liquid food of amount calories.Preferable, this food be have enough volumes and sufficient fat mass and can't be under one's belt the food of stripping and absorption fast.For example, can be on the feed give an object with the dosage of formula (I) chemical compound to the feed back between about two (2) hours in first three ten (30) minutes.Preferable, get final product giving construction (I) chemical compound after the back feed reaches about 30 (30) minutes on the feed.
As used herein, term " is not followed food " or " fasting " refers to for example administration precontract one (1) hour or the food of not taking food for more time, or the state of about two (2) hours of feed back or longer time.
In a preferred embodiments of the present invention, medical composition of the present invention is the supersaturation system.Term " supersaturation system " refers to the big system of concentration that can exist when active ingredient compound concentration in the solution is than balance.
WO2006/122806 describes the imidazoquinolie derivant, and its grade suppresses lipid kinase (as the PI3-kinases) activity.Be suitable for appointment imidazoquinolie derivant of the present invention, their preparation and the suitable medical composition that contains them and can and comprise formula (I) chemical compound referring to WO2006/122806
Figure BDA00003273913900071
Wherein
R 1Be naphthyl or phenyl, wherein this phenyl is through being independently selected from down one or two substituent groups replacements of group: halogen atom; The low alkyl group that is unsubstituted or replaces through halogen atom, cyano group, imidazole radicals or triazolyl; Cycloalkyl; The amino that one or two substituent groups through being independently selected from low alkyl group, low alkyl group sulfonyl, lower alkoxy and lower alkoxy low-grade alkyl amino replace; Be unsubstituted or piperazinyl that one or two substituent groups through being independently selected from low alkyl group and low alkyl group sulfonyl replace; 2-oxo-Pyrrolizidine base; The lower alkoxy low alkyl group; Imidazole radicals; Pyrazolyl; And triazolyl;
R 2Be O or S;
R 3It is low alkyl group;
R 4Be to be unsubstituted or through halogen atom, cyano group, low alkyl group, lower alkoxy or the pyridine radicals that is unsubstituted or replaces through the piperazinyl that low alkyl group replaces; The pyrimidine radicals that is unsubstituted or replaces through lower alkoxy; The quinolyl that is unsubstituted or replaces through halogen atom; Quinoxalinyl; Or the phenyl that replaces through alkoxyl;
R 5Be hydrogen atom or halogen atom;
N is 0 or 1;
R 6It is oxidation base;
The condition regulation is if n=1 then has radicals R 6The N atom have positive charge;
R 7Be hydrogen atom or amino;
Or its tautomer, or its medical acceptable salt or hydrate or solvate.
The implication that employed group and symbol disclose in having as WO2006/122806 in the definition suc as formula (I) chemical compound, the disclosure case are to incorporate the application's case by reference into.
Unless otherwise indicated, employed basic terminology are preferable otherwise in the context has following implication in this article:
Prefix " rudimentary " expression has at the most and comprises 7, and especially at the most and comprise the group of 4 carbon atoms, mentioned group is straight chain type or the branched chain type that is single or many branching.
When using plural form at chemical compound, salt and fellow, should be considered as also meaning individualized compound, salt or fellow.
In a preferred embodiments, " alkyl " has at the most 12 carbon atoms and specifically is low alkyl group.
" low alkyl group " is preferably has (containing) 1 to (containing) 7, and preferable (containing) 1 be to the alkyl of (containing) 4 carbon atoms, and is the straight or branched type; Preferable, low alkyl group is butyl, as normal-butyl, sec-butyl, isobutyl group, the tert-butyl group; Propyl group is as n-pro-pyl or isopropyl; Ethyl or preferable methyl.
" cycloalkyl " is preferably in the ring has (containing) 3 to the cycloalkyl of (containing) 6 carbon atoms; Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.
The alkyl that replaces through halogen atom is preferably perfluoroalkyl, as trifluoromethyl.
Halogen atom is fluorine, chlorine, bromine or iodine especially, specifically is fluorine, chlorine or bromine.
In view of the compounds that is free form be its salt form such as grade material (comprise can, for example, in the purification of compounds or when identification, are as those salt of intermediate) between substantial connection, so when suitable and expedient, any argumentation about free cpds in context should be considered as also meaning corresponding salt.
Salt is from the formula with basic nitrogen atom (I) chemical compound, and (for example) preferable acid-addition salts with organic or inorganic acid forms, and specifically is medical acceptable salt.Suitable mineral acid is, for example, and halogen acids such as hydrochloric acid, sulphuric acid or phosphoric acid.Suitable organic acid is, for example, carboxylic acid, phosphonic acids, sulfonic acid or sulfamic acid, for example, acetic acid, propanoic acid, sad, capric acid, dodecylic acid, glycolic, lactic acid, fumaric acid, succinic acid, malonic acid, adipic acid, 1,5-pentanedicarboxylic acid., suberic acid, Azelaic Acid, malic acid, tartaric acid, citric acid, aminoacid such as glutamic acid or Radix Asparagi amino acid, maleic acid, hydroxymaleic acid, citraconic acid, cyclohexane-carboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, the 4-aminosallcylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methanesulfonic acid or ethyl sulfonic acid, the 2-ethylenehydrinsulfonic acid, ethane-1, the 2-disulfonic acid, benzenesulfonic acid, the 4-toluenesulfonic acid, the 2-LOMAR PWA EINECS 246-676-2,1, the 5-naphthalenedisulfonic acid, 2-or 3-toluene sulfonic acide, methylsulfuric acid, ethyl sulfuric acid, decyl sulphuric acid, N-cyclohexyl sulfamic acid, the N-methyl-, the N-ethyl-or N-propyl group-sulfamic acid or other organic proton acids, as ascorbic acid.Preferable, formed salt is the 4-toluene fulfonate.
With regard to the purpose of isolated or purified, also can use medical unacceptable salt, for example, picrate or perchlorate.With regard to the purposes for the treatment of, only adopt medical acceptable salt or the free cpds form of pharmaceutical preparation (can use), and be good with these things therefore.
Preferred compounds of the present invention is the chemical compound that is described in specially among the WO2006/122806.Splendid chemical compound of the present invention is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl]-propionitrile and toluene monooxygenase sulfonate (compd A) thereof.2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2,3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-propionitrile and the synthetic of toluene monooxygenase sulfonate thereof are to be described among (for example) WO2006/122806 with embodiment 7 and embodiment 152-3 respectively, this case is to quote its mode in full to incorporate this paper into.Another splendid chemical compound of the present invention is 8-(6-methoxyl group-pyridin-3-yl)-3-methyl isophthalic acid-(4-piperazine-1-base-3-trifluoromethyl-phenyl)-1, and the 3-dihydro-imidazol-is [4,5-c] quinoline-2-one-(compd B) also.8-(6-methoxyl group-pyridin-3-yl)-3-methyl isophthalic acid-(4-piperazine-1-base-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-also the synthetic of [4,5-c] quinoline-2-one-are to be described among (for example) WO2006/122806 with embodiment 86.
Should (etc.) the treatment chemical compound is to treat effective dose or concentration is present in the medical composition of the present invention.This treatment effective dose or concentration are known by doctor, clinicist or the veterinary who has the knack of this area substantially, and this amount or concentration will change with employed therapeutic combination and indication to be treated.The treatment effective dose of this treatment chemical compound or concentration further are to decide on various other factors, and these factors comprise patient's type, species, age, body weight, sex and medical condition; The seriousness of the patient's condition to be treated; The administration path; Patient's kidney liver function; And the particular compound that adopts.Substantially the doctor, clinicist or the veterinary that have the knack of this area can determine and regulation prevention, antagonism or the required active drug amount of prevention patient's condition progress easily.Drug level is fallen within the scope that produces usefulness the dynamic (dynamical) scheme of demand based target position to utilization ratio of drug with best degree of accuracy.This scheme need consider to treat distribution, balance and the elimination of chemical compound.
For example, it is in about 3mg to about 5g that treatment chemical compound or its medical acceptable salt shown in the formula (I) are used for the patient's of about 70kg body weight dosage, about 10mg is to about 1.5g, preferable about 100mg is to about 1600mg/ people, preferable about 800mg is to about 1600mg/ people, and preferable about 800mg is to about 1400mg/ people, and preferable about 100mg is to about 1000mg/ people/day, or about 200mg is to the scope of about 400mg/ people/day, and can have 1 to 3 time of same amount preferable being divided into (for example) and singly give.Generally speaking, half of children taking adult dosage.
In an embodiment, the formula in the medical composition (I) treatment chemical compound is crystal form.Preferable, this medical composition comprises the crystal form of compd A.
According to the present invention, treat chemical compound shown in the formula (I), especially compd A or compd B are with about 1 to about 99%, preferable about 30 to about 60%, and even better about 35% to about 60% amount exist.
Nonionic surfactant vitamin E-TPGS (water dissolvable D-alpha-tocopherol polyethanediol succinate) is amphipathic excipient, and it is the water dissolvable derivant of natural source vitamin E.These things comprise, for example, from Eastman Fine Chemicals Kingsport, those materials that Tex., USA purchase has about 1000 aggregate number.Except as the water dissolvable vitamin E source, to have recommended vitamin E-TPGS is used as the hydrophilic nonionic surfactant, its grade can be used as emulsifying agent, solubilizing agent and bioavailability reinforcing agent.It is believed that nonionic surfactant vitamin E-TPGS for the present invention helps to reduce or suppress precipitation suc as formula (I) chemical compound.
Vitamin E-TPGS or PEGization vitamin E are vitamin e derivatives, and wherein the Polyethylene Glycol subelement is the ring hydroxyl place that is connected in the vitamin E molecule by succinic diester.Vitamin E-TPGS.Comprising the ester of various chemical parts and the various vitamin Es-TPGS chemical derivative of ehter bond is to be contained in the definition of vitamin E-TPGS.
Special good person is the D-alpha-tocopherol polyethanediol succinate that contains 500 to 6000Da the PEG molecular weight of the having an appointment (derivant of vitamin E-TPGS).In a preferred embodiments, be D-alpha-tocopherol cetomacrogol 1000 succinate (vitamin E-TPGS, tocopherol chlorine is given birth to (tocopherlosan)) according to vitamin E-TPGS used in the present invention.
According to the present invention, vitamin E-TPGS be with said composition about 15 to about 80 weight %, for example, about 15 to about 45%, about 15 to about 35%, or about 30% to about 45% amount is present in this medical composition.In an embodiment, vitamin E-TPGS is present in the said composition with generation with about 15 to about 35% amount to have the medical composition that uniform grading in fact distributes.
Stripping reinforcing agent of the present invention is the combination in any that is selected from Polyethylene Glycol (PEG), poly(ethylene oxide) and above material.
In preferred embodiments, this stripping reinforcing agent is PEG, and it is to meet formula H (OCH basically 2CH 2) nThe ethylene oxide polymer of OH, wherein n represents the mean molecule quantity of polymer.
The PEG type that can be used among the present invention can its state of matter be classified, that is, this material is to exist with solid or liquid form under room temperature and normal pressure.As used herein, " liquid PEG " refers to have and makes this material be the PEG of the molecular weight of liquid or semi-liquid stage under room temperature and normal pressure.For example, having 100 PEG to the molecular weight below 950 is liquid PEG.These PEG comprise, but are not restricted to PEG 200, PEG 300, PEG 400, PEG 600 and PEG 800.
As used herein, " solid PEG " refers to have and makes this material be the PEG of solid-state molecular weight under room temperature and normal pressure.For example, the PEG with molecular weight of 950 to 10,000 is solid PEG.These PEG comprise, but are not restricted to PEG 1000, PEG 1550, PEG 2000, PEG 3000, PEG 3350, PEG 4000 or PEG 8000.Useful especially solid PEG is those things with 1,450 to 8,000 molecular weight.Especially can be used as solid PEG person and be PEG 1450, PEG 3350, PEG 4000, PEG 8000, its etc. derivant and etc. mixture.Can (Dow Chemicals, Danbury CT) purchase the PEG with various molecular weight with CARBOWAX SENTRY series from Dow Chemical.
Have with the structure of PEG unanimity but the different poly(ethylene oxide) (PEO) of chain length and end group also is applicable among the present invention.Each grade PEO purchases with POLYOX from Dow Chemical.It is about 100,000 to 7,000 that PEO (for example) has, 000 molecular weight.Stripping reinforcing agent among the present invention can comprise the combination in any of PEG, PEO and above material.
In preferred embodiments, the stripping reinforcing agent is solid PEG.The best is the solid PEG of PEG 3350.
In another illustrative embodiments, the stripping reinforcing agent of supporting agent is made up of single stripping reinforcing agent, for example, and solid PEG, for example, PEG 1450, PEG 3350, PEG 4000 and PEG 8000.For example, if medical composition comprises PEG 3350, then this medical composition can not contain other stripping reinforcing agents.
In another illustrative embodiments, the stripping reinforcing agent of supporting agent is made up of the mixture of solid PEG.For example, the stripping reinforcing agent comprise PEG 1450, PEG 3350, PEG 4000, PEG 8000, its etc. derivant and etc. any combination and mixture.
According to the present invention, this stripping reinforcing agent be with said composition about 1 to about 15 weight %, for example, about 1% to about 10%, for example, about 4% to about 8%, for example, about 4% to about 7% amount is present in this medical composition.
In a preferred embodiments, this medical composition is namely to release compositions.
The invention further relates to a kind of method of making medical composition of the present invention, this method forms these granules and subsequently these particle formulation is become peroral dosage form by melt pelletization.
As used herein, term " melt pelletization " refers to comprise the compound processing procedure of following steps:
(a) form shown in the formula (I) treatment chemical compound and at least a nonionic surfactant vitamin E-TPGS and be selected from the mixture of at least a stripping reinforcing agent of the combination in any of Polyethylene Glycol (PEG), poly(ethylene oxide) and above material,
(b) utilize extruder or other suitable equipment (for example, the chuck high shear mixer) that this mixture is carried out pelletize, simultaneously the temperature of this mixture is heated above the softening temperature of this nonionic surfactant vitamin E-TPGS; As used herein, " softening temperature " is to instigate the viscosity degradation speed of this nonionic surfactant as the temperature of the function of temperature; And
(c) for example, under control speed, make granule be cooled to room temperature.
Can (for example) by the container that uses fluidized bed pelletizer or the high shear mixing member is installed heat and hybrid (I) chemical compound and at least a surfactant vitamin E-TPGS and at least a stripping reinforcing agent of combination in any that is selected from Polyethylene Glycol (PEG), poly(ethylene oxide) and above material with formation melt pelletization granule.Vitamin E-TPGS be with said composition about 15 to about 80 weight %, for example, about 15 to about 45%, about 15 to about 35%, or about 30% to about 45% amount is present in this medical composition.The stripping reinforcing agent be with said composition about 1 to about 15 weight %, for example, about 1% to about 10%, for example, about 4% to about 8%, for example, about 4% to about 7% amount is present in this medical composition.Formula (I) chemical compound specifically is compd A or compd B, can about 1 to about 99%, preferable about 30 to about 60%, and even better about 35% to about 60% amount exist.
Extruder can be used for implementing this melt pelletization processing procedure.Generally speaking, extruder is included in (a bit) swingle in the stationary magazine creel, and mould is positioned at this a end.By make this (etc.) bar is at the tube internal rotation, along the whole length distributed composite material (for example, treatment chemical compound, hangover material and any other required excipient) of this bar.Conceptive, this extruder can be divided at least three sections: pull-on section; Heated zones and metering section.In this pull-on section, with raw material from (for example) hopper feed to this extruder.Raw material can be added directly to this hopper and need not solvent.In heated zones, raw-material temperature is heated above the softening temperature of hangover material.The metering section is to be positioned at the heated zones downstream, in this metering section, composite material is extruded the concrete shape of formation by a mould, for example, and granule or material bar, and further grind with the formation granule.The type that is particularly useful for the extruder among the present invention be single-, two-and many bars extruder, its grade optionally disposes the kneading blade.Any kind grinder that can this area general technology person is known is used for the present invention, for example, uses the Frewitt paddle type mill grinder of the 2mm screen cloth of 2000rpm speed.
In order to make medical composition of the present invention, to about 10:1, for example, treat chemical compound and nonionic surfactant vitamin E-TPGS shown in the ratio fusion formula (I) of 1:1,1:2,1:9,2:6 or 3:2 with the about 1:10 of scope.Preferable, this ratio is in the scope of about 1:1 or 1:2.
Can be between the period of heating or carry out component afterwards and mix.For example, can at first mix these components and fusion subsequently, perhaps mix simultaneously and fusion.
In an embodiment, method of the present invention comprises step: (a) formula that will all measure (I) treatment chemical compound, nonionic surfactant vitamin E-TPGS and be selected from Polyethylene Glycol (PEG), poly(ethylene oxide) and above material combination in any the combination of stripping reinforcing agent or mix, (b) (for example utilize extruder or other suitable equipment, the chuck high shear mixer) this mixture is implemented pelletize, simultaneously with this mixture heated to the low product temperature of fusing point (about 38 ℃ to about 41 ℃) than vitamin E-TPGS; Reach and (c) make granule under (for example) control speed, be cooled to room temperature.
In another embodiment, method of the present invention comprises nonionic surfactant vitamin E-TPGS that step (a) will all measure and is divided into first and second portion, (a) formula that will all measure (I) treatment chemical compound, nonionic surfactant vitamin E-the TPGS of first and all amount be selected from Polyethylene Glycol (PEG), the combination of stripping reinforcing agent or the mixing of the combination in any of poly(ethylene oxide) and above material, (b) (for example utilize extruder or other suitable equipment, the chuck high shear mixer) this mixture is implemented pelletize, simultaneously second portion nonionic surfactant vitamin E-TPGS slowly is added into this mixture and makes the product temperature maintenance be lower than about 38 ℃, and (c) make granule under (for example) control speed, be cooled to room temperature.This area general technology person can determine the appropriate amount of first and second portion vitamin E-TPGS.Preferable, when beginning with the second portion nonionic surfactant be heated to about 50 ℃ to about 70 ℃ temperature.
Between granulation stage, with this mixture heated to than the low temperature of melt temperature (about 38 ℃ to about 41 ℃) of vitamin E-TPGS.The temperature of mixture self is called " product temperature ".Preferable, this product temperature is kept between granulation stage and is lower than about 38 ℃.
After the cooling, can grind these granules and screening by sieve subsequently.The suitable particle diameter of granule comprises, but is not restricted to, and about 0.2 to about 3mm, and about 0.5 to about 2.5mm, and about 1 to about 2mm, or about 1.25 to about 2mm.In case obtain the melt pelletization granule, then these particle formulation become solid oral dosage form (for example, tablet, pill, buccal tablet, capsule sheet, capsule or medicine bag) or liquid oral dosage form (for example, beverage, solution or beverage).Preferable, these particle formulation are become capsule or medicine bag.But the artificially is particles filled to capsule or medicine bag with these.Perhaps can utilize the Zinazi packaging machine with particles filled to capsule.
The invention further relates to a kind of peroral dosage form that comprises the medical composition of the chemical compound for the treatment of shown in the formula (I), said composition comprises granule, these granules comprise treats chemical compound (vide infra) shown at least a formula (I), it specifically is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2,3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-propionitrile or 8-(6-methoxyl group-pyridin-3-yl)-3-methyl isophthalic acid-(4-piperazine-1-base-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-also [4,5-c] quinoline-2-one-, or its etc. tautomer, or its etc. the medicine acceptable salt, or hydrate or solvate; At least a nonionic surfactant of the amount of said composition about 15 to about 80 weight %, this surfactant is vitamin E-TPGS; And be selected from least a stripping reinforcing agent of the combination in any of Polyethylene Glycol, poly(ethylene oxide) and above material.Can be used for peroral dosage form of the present invention and comprise solid or liquid dosage form.The example of suitable solid oral dosage form comprises, but is not restricted to tablet, pill, buccal tablet, capsule sheet, capsule or medicine bag.The example of suitable liquid dosage form comprises, but is not restricted to beverage, solution or beverage.
In preferred embodiments, peroral dosage form is solid oral dosage form.Preferable, this peroral dosage form is capsule or medicine bag.According to the present invention, medical composition can be encapsulated in and be dissolved in the mouth, in the list or multiple dose medicine bag in Sublingual, or prepares in the tablet mode.
Can be with tablet as the suitable for oral administration dosage form.Make after granule cooling and the screening, can and suppress or be molded as the monolithic tablet subsequently by this mixture of the further fusion of (for example) V-blender.This tablet can optionally coat with functional or non-functional coating as known in the art.The example of packaging technique comprises, but is not restricted to sweet tablet, film coating, microcapsule and pressed coated.Types of coatings comprises, but is not restricted to casing, sustained release coating and controlled release coat.
Any capsule as known in the art can be used for encapsulation medical composition of the present invention.One example of this capsule is hard gelatin capsule, for example, and by Capsugel of Morris Plains, the CONI-SNAP of N.J. manufacturing.The suitable size of these capsules comprises, but is not restricted to 00 to No. 5.
Can be with the dosage form of any medicine bag as known in the art as medical composition of the present invention.One example of this medicine bag is by the MONUROL of Zambon Switzerland Ltd. manufacturing (fosfomycin amine butantriol) medicine bag.
But can use any liquid that the object safety clothes use or semiliquid beverage/food to give medical composition of the present invention.The general technology person will understand this liquid or the semiliquid beverage/food of formula (I) chemical compound that how to calculate and contain suitable dosage.In this embodiment, the pharmaceutical compound granule can be mixed in liquid beverage (for example, water, milk or soda water) or the semi-liquid foodstuff (for example, yoghourt).
Peroral dosage form of the present invention can optionally further comprise other known pharmaceutical excipient.The example of these excipient comprises, but is not restricted to disintegrating agent, adhesive, lubricant, fluidizer, stabilizing agent and filler, diluent, coloring agent, flavoring agent and antiseptic.This area general technology person can be at the concrete required character of solid oral dosage form, by normal experiment and need not too much burden and select one in the above-mentioned excipient or many persons.The amount of employed each excipient can change in the known scope of this area.Below incorporate this paper into way of reference list of references will disclose technology and the excipient that is used for formulate oral dosage forms.Referring to " handbook of pharmaceutical excipients " (The Handbook of Pharmaceutical Excipients), the 4th edition, people such as Rowe write, American Pharmaceutical Association (American Pharmaceuticals Association) (2003); And " Lei Mingdun pharmaceutical science and put into practice " (Remington:the Science and Practice of Pharmacy), the 20th edition, Gennaro is compiling, Lippincott Williams; Wilkins (2003).
Can by before melt pelletization or during one or more known excipient incorporated in the starting mixt or by with one or more known excipient with the granule combination that is peroral dosage form and these other known excipient are optionally incorporated in the peroral dosage form.In one embodiment of back, can reach and suppress or be molded as tablet subsequently by the mixture of the further fusion of (for example) V-blender through combination, for example the monolithic tablet by encapsulated, or is filled in the medicine bag.
The example that medicine can be accepted disintegrating agent comprises, but is not restricted to starch; Clay; Cellulose; Alginate; Natural gum; Cross linked polymer, for example, crosslinked polyethylene Pyrrolizidine ketone or crospovidone, for example, available from the extraordinary product in the world (International Specialty Products, Wayne, POLYPLASDONE XL WJ); Cross-linked carboxymethyl fiber sodium or cross-linked carboxymethyl cellulose sodium, for example, from the AC-DI-SOL of FMC; And cross-linked carboxymethyl cellulose calcium; Soybean polysaccharide; And guar gum.Disintegrating agent can said composition about 0% to about 10 weight % amount exist.In an embodiment, disintegrating agent is that about 0.1% amount to about 5 weight % with said composition exists.
The example that medicine can be accepted adhesive comprises, but is not restricted to starch; Cellulose and derivant thereof, for example, microcrystalline Cellulose, for example, from FMC (Philadelphia, PA) AVICEL PH, hydroxypropyl cellulose, hydroxyethyl-cellulose and hydroxypropyl emthylcellulose, from Dow Chemical (Dow Chemicals Corp., Midland, METHOCEL MI); Sucrose; Dextrose; Corn syrup; Polysaccharide; And gelatin.Adhesive can said composition about 0% to about 50%, for example, the amount of 2 to 20 weight % exists.
Medicine can accept lubricant and the medical example that can accept fluidizer includes, but are not limited to silica colloidal, magnesium trisilicate, starch, Talcum, three alkali calcium phosphates, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, magnesium oxide, Polyethylene Glycol, powdery cellulose and microcrystalline Cellulose.Lubricant can said composition about 0% to about 10 weight % amount exist.In an embodiment, lubricant can said composition, and about 0.1% to about 1.5 weight % amount exists.Fluidizer can about 0.1% to about 10 weight % amount exist.
Medicine can accept filler and the medical example that can accept diluent comprises, but be not restricted to icing sugar, sompressible sugar, glucosan, dextrin, dextrose, lactose, mannitol, microcrystalline Cellulose, powdery cellulose, Sorbitol, sucrose and Talcum.Filler and/or diluent can, for example, exist with about 0% amount to about 80 weight % of said composition.
Can in the standard clinical test, observe the effectiveness of all medical compositions of the present invention, for example, produce the known indications of the drug dose of the effective haemoconcentration for the treatment of for the treatment of chemical compound; For example, using dosage is that about 3mg is to about 5g, about 10mg is to about 1.5g, preferable about 100mg is to about 1600mg/ people, preferable about 800mg is to about 1600mg/ people, and preferable about 800mg is to about 1400mg/ people, and preferable about 100mg is to about 1000mg/ people/day, or about 200mg is to about 400mg/ people/day, and has 1 to 3 part of single dose of same amount preferable being divided into (for example).
Medical composition of the present invention can be used for treating proliferative disease, especially respond to the proliferative disease of lipid kinase and/or PI3k kinase-associated protein matter kinase inhibition, these diseases are to be selected from optimum or malignant tumor, the brain cancer, renal carcinoma, hepatocarcinoma, adrenal carcinoma, bladder cancer, breast carcinoma, gastric cancer, gastric tumor, ovarian cancer, colon cancer, rectal cancer, carcinoma of prostate, pancreatic cancer, pulmonary carcinoma, cancer of vagina or thyroid carcinoma, sarcoma, the neuroglia blastoma, multiple myeloma or human primary gastrointestinal cancers specifically are colon cancer or colorectal adenomas or tumor of head and neck, the epidermis hyperplasia, carcinoma of endometrium, psoriasis, prostatic hyperplasia, interior anything superfluous or useless, anything superfluous or useless in the epithelium, lymphoma, breast carcinoma or leukemia.Other diseases comprises examining steps on (Cowden) syndrome, Lai Ermite-Du Baisi (Lhermitte-Dudos) disease and Ban Nayang-Zong Ana (Bannayan-Zonana) syndrome or the disease of PI3K/PKB path abnormal activation wherein.Can be to be disclosed among the WO2006/122806 by the other diseases of medical composition treatment of the present invention, this case be to incorporate this paper by reference into.The best, the disease for the treatment of are the proliferative diseasees that responds to the PI3 kinase inhibition.
Medical composition of the present invention can be further used for treating those mTOR kinases that disclose among the WO2008/103636 and rely on disease, and this case is to incorporate this paper by reference into.With the mTOR kinase activity regulate bad have establish or syndrome that potential molecule is related is to describe (for example) in " people such as K.Inoki; Disregulation of the TSC-mTOR pathway in human disease (imbalance of TSC-mTOR path in human diseases), Nature Genetics, the 37th volume, 19-24 "; " D.M.Sabatini; MTOR and cancer:insights into a complex relationship (mTOR and cancer: have an X-rayed its complex relationship), Nature Reviews, the 6th volume, 729-734 "; And " people such as B.T.Hennessy; Exploiting the PI3K/Akt pathway for cancer drug discovery (being cancer drug exploratory development PI3K/Akt path), Nature Reviews, the 4th volume, 988-1004 " in; these documents (comprising the list of references of wherein quoting from) are to incorporate into by reference in the application's case; and following treatment of conditions: organ or tissue's transplant rejection; for example, (for example) heart, lung, the heart-lung associating, liver, kidney, pancreas, skin or corneal graft receiver's treatment; The anti-host disease of implant is after bone marrow transplantation; The restenosis epiloia; Lymphatics of lung proliferation of smooth muscle disease; Retinitis pigmentosa; Autoimmune disease comprises encephalomyelitis, insulin-dependent diabetes, lupus, dermatomyositis, arthritis and rheumatism; Anti-steroid acute lymphoblastic leukemia; Fiber disease comprises scleroderma, pulmonary fibrosis, renal fibrosis, cystic fibrosis; Pulmonary hypertension; Immunomodulating; Multiple sclerosis; The VHL syndrome; Card is (Carney) syndrome how; Familial adenomatous polyposis; Juvenile polyposis syndrome; The birt-Hogg-Duke syndrome; The familial hypertrophic cardiomyopathy; Wulff-parkinson-White's disease syndrome (Wolf-Parkinson-White syndrome); Neurodegenerative disease accumulates disease/Ba Dengshi disease (Batten disease) (children's's nerve degeneration) as parkinson, Heng Dingdunshi disease, A Zihai Mo's disease and the dementia that is caused by the τ sudden change, 3 type spinocerebellum deficiency disorders, the motor neuron disease, the neuron wax sample lipofuscin that are caused by the SOD1 sudden change; Moist and dryness macular degeneration; Wasting (atrophy, cachexia) reaches such as the myopathy that reaches Nong Shi disease (Danon ' s disease); Antibacterial and viral infection comprise that tulase, A group B streptococcus, I type HSV, HIV infect; Neurofibromatosis comprises 1 type neurofibromatosis; Pu Zijie Floex syndrome (Peutz-Jeghers syndrome) or its wait other combination in any.
Medical composition of the present invention can be enough to provide about 200 to about 70 in object blood plasma, tautomers such as the formula of the AUC of 000ng*h/mL (I) chemical compound or its, or its etc. the medicine acceptable salt, or the amount of hydrate or solvate gives.In other these embodiments, the amount that gives is enough to provide about AUC of 500 to 43,000ng*h/mL in object blood plasma.In other these embodiments, in object blood plasma, AUC is about 1,000 to 21,000ng*h/mL.
Medical composition of the present invention can be contained in capsule or the medicine bag, this capsule or medicine bag are enough to provide about 200 to about 70 in this object blood plasma after object is given, the formula of the AUC of 000ng*h/mL (I) chemical compound or its tautomer, or its medical acceptable salt or hydrate or solvate.In other these embodiments, the amount that gives is enough to provide about AUC of 500 to 43,000ng*h/mL in object blood plasma.In other these embodiments, in object blood plasma, AUC is about 1,000 to 21,000ng*h/mL.
Medical composition of the present invention also can be loaded in the medicine bag, this medicine bag is enough to provide at least about 400 to about 15 the formula of the AUC of 000ng*h/mL (I) chemical compound or its tautomer or its medical acceptable salt or hydrate or solvate object being given the back in this object blood plasma.
The invention further relates to a kind of to suffering from the method that can treat by the object of disease, the patient's condition or imbalance of the compounds for treating for the treatment of shown in the formula (I), this method comprise will the treatment effective dose medical composition of the present invention need the object of this treatment.Above-mentioned disease and pharmacokinetic characteristic be the present invention in this respect other embodiments and be to incorporate this paper by reference into.
In addition; the present invention relates to comprise formula (I) chemical compound; the medical composition of the present invention that specifically is compd A or compd B is used for the treatment of purposes in the medicament of proliferative disease in manufacturing; this proliferative disease is selected from optimum or malignant tumor; the brain cancer; renal carcinoma; hepatocarcinoma; adrenal carcinoma; bladder cancer; breast carcinoma; gastric cancer; gastric tumor; ovarian cancer; colon cancer; rectal cancer; carcinoma of prostate; pancreatic cancer; pulmonary carcinoma; cancer of vagina or thyroid carcinoma; sarcoma; the neuroglia blastoma; multiple myeloma or human primary gastrointestinal cancers specifically are colon cancer or colorectal adenomas or tumor of head and neck; the epidermis hyperplasia; carcinoma of endometrium; psoriasis; prostatic hyperplasia; interior anything superfluous or useless; anything superfluous or useless in the epithelium; lymphoma; breast carcinoma or leukemia; examine and step on (Cowden) syndrome; Lai Ermite-Du Baisi (Lhermitte-Dudos) disease; Ban Nayang-Zong Ana (Bannayan-Zonana) syndrome or PI3K/PKB path abnormal activation wherein.The invention further relates to and comprise formula (I) chemical compound, specifically is the purposes of medical composition of the present invention in the medicament of the dependence of the mTOR kinases described in making treatment as WO2008/103636 disease of compd A or compd B.
The invention further relates to a kind of medicine box, this medicine box comprises the medicinal composition for oral use that (a) comprises granule, these granules comprise at least a nonionic surfactant of the amount for the treatment of chemical compound, about 15 to the 80 weight % of said composition shown in the formula (I), and this surfactant is vitamin E-TPGS; And be selected from least a stripping reinforcing agent of the combination in any of Polyethylene Glycol, poly(ethylene oxide) and above material; Reach (b) written explanation, wherein these written explanations are pointed out, take between about 2 hours after this medicinal composition for oral use can extremely be taken food on the feed in preceding 30 minutes.Preferable, these written explanations point out that this medicinal composition for oral use takes between about 30 minutes to taking food after can be on the feed.
This medicine box can further comprise about 3mg to about 5g in aforesaid written explanation, about 10mg is to about 1.5g, preferable about 100mg is to about 1600mg/ people, preferable about 800mg is to about 1600mg/ people, preferable about 800mg is to about 1400mg/ people, preferable about 100mg is to about 1000mg/ people/day, or about 200mg about 400mg/ people/day extremely, preferable 1 to the 3 part of single dose that can (for example) has same amount that is divided into.
The invention further relates to the purposes of medical composition of the present invention in treatment proliferative disease or mTOR kinases dependence disease, this purposes comprises the object that medical composition is had demand with food, this medical composition comprises granule, and these granules comprise shown in the formula (I) treats chemical compound; At least a nonionic surfactant of the amount of about 15 to the 80 weight % of said composition, this surfactant is vitamin E-TPGS; And be selected from least a stripping reinforcing agent of the combination in any of Polyethylene Glycol, poly(ethylene oxide) and above material, cause comparing when not following food to give object with this medical composition, the bioavailability that gives this medical composition up-to-date style (I) chemical compound with food increases.
In an embodiment, provide medical composition of the present invention to rely on purposes in the disease at treatment proliferative disease or mTOR kinases, wherein this medical composition there are the object of demand, wherein C with food MaximumDo not increase when following food to give this medical composition.In another embodiment, C MaximumDo not increase at least 20% when following food to give this medical composition.
In an embodiment, provide a kind of medical composition of the present invention to rely on purposes in the disease at treatment proliferative disease or mTOR kinases, wherein this medical composition there are the object of demand, wherein AUC with food FinallyDo not increase when following food to give this medical composition.In another embodiment, AUC FinallyDo not increase at least 15% when following food to give this medical composition.
The invention further relates to the purposes of medical composition of the present invention in treatment proliferative disease or mTOR kinases dependence disease, this purposes comprises the medical composition that will comprise granule has the object of demand with food, and these granules comprise shown in the formula (I) treats chemical compound; At least a nonionic surfactant of the amount of about 15 to the 80 weight % of said composition, this surfactant is vitamin E-TPGS; And be selected from least a stripping reinforcing agent of the combination in any of Polyethylene Glycol, poly(ethylene oxide) and above material, wherein with following food formula (I) is not compared when chemical compound gives object, given the bioavailability increase that this medical composition causes formula (I) chemical compound with food.
In an embodiment, provide a kind of medical composition of the present invention to rely on purposes in the disease at treatment proliferative disease or mTOR kinases, wherein this medical composition there are the object of demand, wherein C with food MaximumDo not increase when following food to give this formula (I) chemical compound.In another embodiment, C MaximumDo not increase at least 20% when following food to give this formula (I) chemical compound.
In an embodiment, provide a kind of medical composition of the present invention to rely on purposes in the disease at treatment proliferative disease or mTOR kinases, wherein this medical composition there are the object of demand, wherein AUC with food FinallyDo not follow food that this formula (I) is increased when chemical compound gives object.In another embodiment, AUC FinallyDo not increase at least 15% when following food to give this formula (I) chemical compound.
The invention further relates to a kind of method for the treatment of proliferative disease or mTOR kinases dependence disease, this method comprises the object that the medical composition of the present invention that will comprise formula (I) chemical compound for the treatment of effective dose with food has demand, wherein compare when not following food to give object with this medical composition, give the bioavailability that this medical composition causes formula (I) chemical compound with food and increase.
In an embodiment, a kind of method that proliferative disease or mTOR kinases rely on disease for the treatment of is provided, this method comprises the object that the medical composition of the present invention that will comprise formula (I) chemical compound for the treatment of effective dose with food has demand, wherein AUC FinallyDo not increase when following food to give this medical composition.In another embodiment, AUC FinallyDo not increase at least 15% when following food to give this medical composition.
In an embodiment, a kind of method that proliferative disease or mTOR kinases rely on disease for the treatment of is provided, this method comprises the object that the medical composition of the present invention that will comprise the medical composition for the treatment of effective dose with food has demand, wherein C MaximumDo not increase when following food to give this medical composition.In another embodiment, C MaximumDo not increase at least 20% when following food to give this medical composition.
The invention further relates to a kind of method for the treatment of proliferative disease or mTOR kinases dependence disease, it comprises the object that the medical composition of the present invention that will comprise formula (I) chemical compound for the treatment of effective dose with food has demand, wherein with do not follow food just formula (I) compare when chemical compound gives object, give the bioavailability that this medical composition causes formula (I) chemical compound with food and increase.
In an embodiment, a kind of method that proliferative disease or mTOR kinases rely on disease for the treatment of is provided, it comprises the object that the medical composition of the present invention that will comprise formula (I) chemical compound for the treatment of effective dose with food has demand, wherein AUC FinallyDo not increase when following food to give this medical composition.In another embodiment, AUC FinallyDo not follow food that this formula (I) is increased at least 15% when chemical compound gives object.
In an embodiment, a kind of method that proliferative disease or mTOR kinases rely on disease for the treatment of is provided, it comprises the object that the medical composition of the present invention that will comprise formula (I) chemical compound for the treatment of effective dose with food has demand, wherein C MaximumDo not increase when following food to give this medical composition.In another embodiment, C MaximumDo not follow food that formula (I) is increased at least 20% when chemical compound gives object.
The usefulness that following examples explain, but not be used for the restriction described scope of the invention herein.These embodiment only are intended to prompting and implement method of the present invention.
The employed one-tenth deal of representing with the percentage by weight of medical composition is described in hereinafter among each embodiment.With regard to capsule or medicine bag, when calculating the weight (that is, capsule or medicine bag filler weight) of medical composition, the weight of capsule shells or medicine bag self is got rid of in calculating.
Embodiment 1
Figure BDA00003273913900211
Each person in the above composition is through independent measurement and weighs.Vitamin E-TPGS be available from Yi Siman fine chemicals company (Eastman Fine Chemicals Kingsport, Tex., USA).Mannitol is available from Luo Kaite company (Roquette GMBH).PEG3350 is available from Ke Lai Rehau AG ﹠ Co. (Clariant GMBH).Crospovidone is available from the extraordinary Products Co., Ltd in the world (International Specialty Products Corporation).Then, with vitamin E-TPGS separated into two parts of all measuring, 56% (part 1) of total amount and 44% (part 2).Be loaded in the suitable size container part 1 of vitamin E-TPGS and freeze overnight or use dry ice, and under the medium speed, reach by the Fitzmill homoloid machine screening that is equipped with a #0079 screen cloth carry out dry grinding through freezing vitamin E-TPGS subsequently.
With regard to the pelletize processing procedure, each person in the following composition is loaded into Collette TMGRAL TMIn the suitable size pelletize alms bowl in the high shear mixer: (1) 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2,3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-propionitrile toluene monooxygenase sulfonate, (2) mannitol, (3) crospovidone, (4) PEG 3350, and (5) vitamin E PEG succinate (part 1).Carrying out 5 minutes dry types by the material of the PLOW that is set at low velocity mixes and record mixed-powder temperature.Mixture is cooled off in comminutor until the temperature that obtains to be less than or equal to 22 ℃.
Be loaded into the part 2 of vitamin E-TPGS in the suitable size container and heating reaches 50 ℃ to 70 ℃ temperature range until fusion.
Starting the Collette that PLOW is set at low speed TMGRAL TMBehind the high-shear mixer, the vitamin E-TPGS part 2 with aequum in two (2) minutes is added in the mixture.Make the mixture of gained continue in high shear mixer (PLOW and chipper are set at a high speed) remix one (1) minute.After PLOW and chipper are set at low speed, make mixture continue in high shear granulator, to be mixed to many 25 minutes, until forming suitable granule.Between whole mixing period, the product temperature should be kept and be lower than 38 ℃.Utilize the artificial formed granule of screening of 14 eye mesh screens and place appropriate vessel.
After finishing screening, utilize cryoprobe or dry ice that all granules are cooled to 0 ℃ or lower temperature.The Frewitt GLA agitator that utilization is equipped with 14 eye mesh screens further screening through the granule of cooling to reduce or to remove oversized particles.
Will from above processing procedure obtain through the screening granule be loaded in the suitable size hopper bag of a hopper blender and together fusion 150 change time.After the fusion, that granule is hand-stuff to medicine bag.
Embodiment 2
Figure BDA00003273913900221
Embodiment 2 utilizes the same procedure that discloses as embodiment 1 to implement; Yet final granule is to utilize Zanasi encapsulate machine to be filled in the capsule.
Embodiment 3
Figure BDA00003273913900231
Embodiment 3 utilizes the same procedure that discloses as embodiment 1 to implement; Yet, the D-alpha-tocopherol cetomacrogol 1000 succinate of all measuring is added into original mixture and utilizes 17mm to melt extrude machine by melt extruding the formation granule, utilize the Fitz Homoloid grinder screening with No. 0079 screen cloth subsequently, and last hand-stuff to capsule.273.4mg and 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl-propionitrile toluene monooxygenase sulfonate of 68.4mg distinctly is equivalent to 200mg and 50mg free alkali.
Embodiment 4
Figure BDA00003273913900232
Embodiment 4 utilizes as the same procedure of embodiment 1 to implement; Yet, mannitol or crospovidone are not added in this original mixture.
The research of embodiment 5-dog
Below two kinds of formulation variants be to prepare in the original position mode, give dog then:
* 2-methyl-2-[4-of 68.5mg (3-methyl-2-oxo-8-quinoline-3-base-2,3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-propionitrile toluene monooxygenase sulfonate is equivalent to 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2 of 50mg, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl]-the propionitrile free alkali.
Two preparations all are according to the same procedure manufacturing as embodiment 1; Yet, whole D-alpha-tocopherol cetomacrogol 1000 succinates of amount is added in the original mixture and utilizes 17mm to melt extrude machine, extrude by fusion and form granule and utilize the Fitz Homoloid grinder screening that is equipped with No. 0079 screen cloth subsequently.
2-substep stripping test
Utilize the formula stripping test of 2 steps to estimate independently only to contain the capsule of compd A, formulation variants 1 or 2.This analyzes 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2 that contrast contains 68.5mg/ unit, 3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-(it is equivalent to 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2 of 50mg to propionitrile toluene monooxygenase sulfonate, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl]-the propionitrile free alkali) the stripping overview of capsule under pH2 and pH6.8.
Analyze at this point, the capsule that only contains compd A, formulation variants 1 or variant 2 is placed 900mLpH2HCl and stirs 10 to 100 minutes (wherein stirring fast in about the 60th minute to the 90th minute) at a USP equipment I I with the 50rpm rotation subsequently.When about the 100th minute time point, this medium is adjusted to pH6.8 and 1000ml volume and in a USP equipment I I with the 50rpm rotation, stirs subsequently.Utilizing one 100 μ m Varian full flow filters filtered sample to reach analyzes by HPLC.
As shown in Figure 2, the result of this 2 step formula stripping test is clear confirms that medical composition of the present invention is compared to the stripping of the remarkable improvement compd A of unification compound.In addition, medical composition of the present invention has similar drug release under pH2 and pH6.8, and single compd A has the drug release near 0% under pH6.8.These data confirm that further this medical composition successfully makes compd A maintain supersaturation concentration.
Dog research
In this research, two groups (every group of n=3) male purebred bread beasle dog (is derived from Marshall farm (North Rose, NY) ADME group) orally give contains and is equivalent to (the research argumentation at this point of common 50mg free alkali, be called " 50mg compd A ") 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2 of amount, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl]-two capsules of propionitrile toluene monooxygenase sulfonate.
Each dog weighs 8 to 13kg.During research, dog put in the cage of staying suitable labelling separately and with the continuous number labelling.In when week before administration, weigh up a dog weight.
With regard to administration, each dog in the 1st and 2 group accepts to contain the two capsules of 25mg compd A by the per os tube feed, then feeds and 50mL water.The 1st group of orally give is equivalent to two 25mg capsules of formulation variants 1, and the 2nd group of orally give is equivalent to two 25mg capsules of formulation variants 2.
Before administration and after the administration, collect continuous blood sample from each dog 0.25,0.5,1,2,3,4,6,8 and 24 hour the time.Collect the vein whole blood of about 2mL.Via cephalic vein with blood sample collection to the 2.5mL blood collection tube, and with EDTA as anticoagulant.Sample is carried out centrifugal and isolates blood plasma and be transferred in the polypropylene cryovial.Before analysis, plasma sample is kept at is less than or equal under-20 ℃.
(Eastern Han Dynasty's Nowe (East Hanover, NJ) bioanalysis of carrying out) in the New Jersey is measured the compd A concentration in the blood plasma by the liquid chromatography (LC) of having verified-associating mass spectrography (LC-MS/MS).Following instrument and setting are used for LC-MS/MS:
Instrument: TomTec Quadra 96
LC condition: tubing string: ACE phenyl (ACE Phenyl), 3 μ m, (50 * 4.6mm), Mac-Mod analytical type); Temperature: 30 ℃; Isocratic elution: [A:0.1% aqueous formic acid, the acetonitrile of B:0.1% formic acid: methanol (50:50 volume) solution, (A:B, 30:70 volume)]; Flow velocity: 1.0mL/ minute; Volume injected: 10 μ L.
LC system: pump: Tianjin, island (Shimadzu) LC-20AD; Automatic sampler: Tianjin, island SIL 20-AC; Baking oven: Tianjin, island CTO 20-AC.
Mass spectrometer: API4000, Applied Biosystems, Inc. (Applied Biosystems)
Mass spectrometer is set: and the MS condition (ESI: source temperature: 450 ℃, voltage: 5500V, holdup time: 150ms is for compd A and [m+4] compd A); Materialization compd A (precursor ions: m/z 470.3; Product ion: m/z 443.1; Impact energy (CE): 49 (eV); Remove a bunch voltage (DP): 146 (eV)); Materialization ISTD (precursor ions: m/z 474.3; Product ion: m/z 447.3; Impact energy (CE): 55 (eV); Remove a bunch voltage (DP): 141 (eV)).
Utilize 5.2 editions programs of non-compartmentation method and WinNonlin (California mountain scene city PC company (Pharsight Corporation, Mountain View, CA)) analytical concentration-time graph.Former compound concentration (the C of record maximum plasma Maximum) and time of origin (T Maximum).Utilize linear trapezoid method then to calculate AUC Finally
Following result studies available from above dog:
Figure BDA00003273913900261
This dog result of study is clear to be shown, absorbs and bioavailability in the body of the remarkable improved treatment chemical compound of medical composition of the present invention.
Embodiment 6
To after the menolipsis or 18 to 55 years old healthy women human volunteer orally give accepting sterilisierende operation be equivalent to 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2 of the dosage of common 25mg free alkali, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl] propionitrile toluene monooxygenase sulfonate.2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2 that will be equivalent to the dosage of common 25mg free alkali, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl] propionitrile toluene monooxygenase sulfonate is with the hard gelatin capsule standard preparation or comprise the mode orally give patient of the hard gelatin capsule (" hard gelatin capsule SDS ") of medical composition of the present invention.
The hard gelatin capsule standard preparation is the medical composition of wet type pelletize, it comprises 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2 of the amount that is equivalent to common 25mg free alkali, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl] propionitrile toluene monooxygenase sulfonate and corresponding following form (wherein this equivalent is the percentage ratio of capsule filler weight):
Figure BDA00003273913900271
136.7mg 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2,3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl] propionitrile toluene monooxygenase sulfonate is equivalent to 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2 of 100mg, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl] the propionitrile free alkali.Hard gelatin capsule SDS comprises 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2 of the amount that is equivalent to common 25mg free alkali, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl] preparation that discloses among propionitrile toluene monooxygenase sulfonate and the corresponding this paper embodiment 3.
Divide following two parts to implement this research: (a) three treatment phases and six orders (n=18) are to test when giving the patient with the hard gelatin capsule standard preparation, informal dinner is to the effect of medicine exposure, and (b) five treatment phases and ten treatment orders (n=20) with contrast hard gelatin capsule standard preparation and hard gelatin capsule SDS, testing drug preparation and the effect of informal dinner is provided.
Each health volunteer is reached the screening in 2 weeks, will be made as baseline period the same day before each time administration, after each time administration, carry out administration and sample collection at least 24 hours the family, after each time administration, carry out at least 7 days removing, and finish research and follow up a case by regular visits to.Health volunteer's overnight fasting, (medicine) being taken before meal is with 25mg (～0.3mg/kg) hard gelatin capsule standard preparation or hard gelatin capsule SDS, then (being feeding) fasting again in 30 minutes after standard 4 hours ante prandiums (that is, on an empty stomach) or informal dinner then.Collect blood in seclected time point in 24 hours after each time administration.Sample is in collecting from the health volunteer on an empty stomach and under the as fed.With regard to giving the hard gelatin capsule standard preparation under the fasting state, medicine exposes 10 hours at the most that can be quantized to after the administration to the open air, and other states of testing can be quantized to 12 hours at the most after the administration.
The vein whole blood sample is carried out centrifugal and isolates serum or blood plasma.Shifting with liquid chromatography (LC)-associating mass spectrography (LC-MS/MS) ((Bioanalytics of bioanalysis company of New Jersey Eastern Han Dynasty Nowe by empirical tests, East Hanover, NJ)) these serum or plasma sample are kept at before analyzing≤-15 ℃ under.The value representation that will be lower than the quantification lower limit of about 1ng/mL is 0.0ng/mL.Be limited to about 1ng/mL under quantizing.
Utilize non-compartmentation method (Pharsight WinNonlin5.2 version) analytical concentration-time graph.AUC 0- FinallyBe to the concentration-time curve below area that can measure concentration at last.AUC 0-is unlimitedIt is the concentration-time curve below area that is extrapolated to infinity.C MaximumBe maximum (peak value) concentration behind the oral administration.T FinallyIt is the time that finally can measure concentration.T MaximumIt is the time that oral administration reaches maximum (peak value) concentration afterwards.
Following result is available from above research:
Figure BDA00003273913900281
Under fasting state, the SDS capsule preparations produces average total medicine exposure (AUC of similar HG capsule preparations 0-is unlimited) and average maximum medicine exposure (C Maximum).The geometrical mean of hard gelatin capsule SDS when 90%CI is in no effect boundary (0.8 to 1.25), and therefore, under fasting state, hard gelatin capsule standard preparation and hard gelatin capsule SDS are that biofacies is worked as.
Yet under fasting state, the transmutability of the grand mean medicine exposure of hard gelatin capsule SDS is less than hard gelatin capsule standard preparation (46% couple 68% CV AUC 0-is unlimited), illustrate that the medicine exposure of hard gelatin capsule SDS has positive interaction.With regard to the hard gelatin capsule standard preparation under the feeding informal dinner, the transmutability of grand mean medicine exposure is 51%, and the drug absorption concordance of feeding food improvement hard gelatin capsule standard preparation is described.Under the feeding informal dinner, the transmutability of the grand mean medicine exposure of hard gelatin capsule SDS is also improved (46% couple 40% CV AUC 0-is unlimited).
During the feeding informal dinner, the total and maximum average medicine exposure of hard gelatin capsule SDS is all improved than hard gelatin capsule standard preparation (under fasting and as fed).Based on the geometrical mean ratio, under fasting state, use hard gelatin capsule standard preparation improvement 40% (90% confidence interval 1.16-1.70) and maximum average medicine exposure improvement 31% (90% confidence interval 1.03-1.67) at the grand mean medicine exposure that uses the SDS capsule preparations to produce under the feeding informal dinner.In addition, under the feeding informal dinner, grand mean medicine exposure is improved to 55.2ng*h/ml (using hard gelatin capsule SDS) from 45.8ngh/ml (using the hard gelatin capsule standard preparation), has increased by 20%, and the increase of this explanation medicine exposure not only causes because of the effect of food.Under the feeding informal dinner, maximum average medicine exposure (C Maximum) improve to 18.3ng/ml (using hard gelatin capsule SDS) from 14.6ng/ml (using the hard gelatin capsule standard preparation), increased by 25%, confirm that further the increase of medicine exposure not only causes because of the effect of food.
In addition, under the feeding informal dinner, use the SDS capsule preparations to use hard gelatin capsule SDS improvement bioavailability (to comprise AUC than fasting state 0-is unlimited, AUC FinallyAnd C Maximum).
Embodiment 7
To comprise hard gelatin capsule (the research argumentation at this point of medical composition of the present invention, be called " special delivery system capsule " or " SDS capsule ") or medicine bag (research discuss, be called " special delivery system medicine bag " or " SDS medicine bag ") the at this point orally give that the comprises medical composition of the present invention patient that suffers from transitivity/late period solid tumor.2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl with Sq]-propionitrile toluene monooxygenase sulfonate gives each patient.
In this research, with 2-methyl-2-[4-(the 3-methyl-2-oxo-8-quinoline-3-base-2 that contains the total amount that is equivalent to the 1000mg free alkali, 3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-11 (11) patients of SDS capsule for treating of propionitrile toluene monooxygenase sulfonate, with 2-methyl-2-[4-(the 3-methyl-2-oxo-8-quinoline-3-base-2 that contains the total amount that is equivalent to the 800mg free alkali, 3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-six (6) patients of SDS capsule for treating of propionitrile toluene monooxygenase sulfonate, and 2-methyl-2-[4-(the 3-methyl-2-oxo-8-quinoline-3-base-2 to contain the total amount that is equivalent to the 400mg free alkali, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl]-five (5) patients of SDS capsule for treating of propionitrile toluene monooxygenase sulfonate.The SDS capsule that is used for this research can obtain to be equivalent to the preparation that discloses among the dosage of 200mg free alkali and the corresponding this paper embodiment 3.This SDS capsule is to continue day dosage regimen according to one, food following every day of orally give is arranged once feeding.
With 2-methyl-2-[4-(the 3-methyl-2-oxo-8-quinoline-3-base-2 that contains the total amount that is equivalent to the 800mg free alkali, 3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-six (6) patients of the SDS medicine bag of propionitrile toluene monooxygenase sulfonate treatment, with 2-methyl-2-[4-(the 3-methyl-2-oxo-8-quinoline-3-base-2 that contains the total amount that is equivalent to the 1000mg free alkali, 3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-four (4) patients of the SDS medicine bag of propionitrile toluene monooxygenase sulfonate treatment, with 2-methyl-2-[4-(the 3-methyl-2-oxo-8-quinoline-3-base-2 that contains the total amount that is equivalent to the 1400mg free alkali, 3-dihydro-imidazol-also [4,5-c] quinoline-1-yl)-phenyl]-nine (9) patients of the SDS medicine bag of propionitrile toluene monooxygenase sulfonate treatment, and 2-methyl-2-[4-(the 3-methyl-2-oxo-8-quinoline-3-base-2 to contain the total amount that is equivalent to the 1600mg free alkali, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl]-seven (7) patients of the SDS medicine bag of propionitrile toluene monooxygenase sulfonate treatment.The 800 mg SDS medicine bags that are used for this research can obtain to be equivalent to the dosage of 400mg free alkali and have the compositions that contains the preparation described in 400mg this paper embodiment 1.1000mg, the 1200mg and the 1600mg SDS medicine bag that are used for this research have the compositions that contains preparation of the present invention.In order to give this SDS medicine bag, instruct the patient that these SDS medicine bags are suspended in the glass fresh water (about 1dL), drink content subsequently, reach with about this glass of 0.25dL water rinse then and then drink content, the oral cavity of rinsing is simultaneously swallowed then.This SDS medicine bag is to continue day dosage regimen according to one, food following every day of orally give is arranged once feeding.
Collect the blood sample of respectively studying the patient.The whole blood sample all is to obtain by the indwelling intubate in direct venipuncture or the insertion forearm vein.Point place at fixed time, with the 2mL blood collecting in the pipe that EDTA is housed.Between sampling date, these pipes are kept in the ice-water bath under about 4 ℃≤60 minutes.3 ℃ under 5 ℃, with about 100g these pipes are carried out centrifugal 10 minutes with separated plasma.After centrifugal, immediately 1mL blood plasma is transferred in the 2-mL polypropylene spiral cover pipe that is kept on the dry ice.Before analysis, these pipes are placed be set at＜cryoprobe of-15 ℃.
Utilize the drug level of the liquid chromatography (LC)-plasma sample that associating mass spectrography (LC-MS/MS) analysis obtains of empirical tests.The value representation that will be lower than about 1ng/mL quantification lower limit is 0.0ng/mL.
Following result is available from above research:
Table 1-is with C MaximumWith average [minimum-maximum] expression (N)
Table 2-is with AUC 024With average [minimum-maximum] expression (N)
Under the dosage of 800mg, the T that the SDS medicine bag obtains MaximumCome a little earlier than the SDS capsule, its meansigma methods is between 1.5 and 4 hours, but under 1400mg and 1600mg dosage, it increases to 4 to 6 hours.Accumulated value can change because of different patients.With regard to 800 and 1400mg dosage with regard to, it is more moderate than keeping to add up, 3.7 and 2.7 (averages), but increase to 6.9 under 1600mg.Though exist this to add up, yet average t 1/2Be 4 to 8 hours estimated value, in various dose and follow up a case by regular visits to down no greatest differences.
Show that as the result described in table 1 and 2 exposing to the open air of SDS capsule and the equal improved treatment chemical compound of SDS medicine bag preparation illustrates stripping and the absorption of SDS compositions improvement chemical compound.Unexpectedly, those patients by SDS medicine bag preparation for treating represent more consistent pharmacokinetic profile than the SDS capsule preparations.The transmutability of the grand mean medicine exposure that the SDS medicine bag produces is little than the transmutability that the SDS capsule represents.(referring to Fig. 3, this figure is based on preliminary data and does).

Claims (15)

1. medical composition, it comprises granule, and these granules comprise:
(a) the treatment chemical compound shown in the formula (I)
Figure FDA00003273913800011
Wherein
R 1Be naphthyl or phenyl, wherein this phenyl is to replace by one or two substituent groups that are independently selected from down group: halogen atom; The low alkyl group that is unsubstituted or replaces through halogen atom, cyano group, imidazole radicals or triazolyl; Cycloalkyl; The amino that one or two substituent groups through being independently selected from low alkyl group, low alkyl group sulfonyl, lower alkoxy and lower alkoxy low-grade alkyl amino replace; Be unsubstituted or piperazinyl that one or two substituent groups through being independently selected from low alkyl group and low alkyl group sulfonyl replace; 2-oxo-Pyrrolizidine base; The lower alkoxy low alkyl group; Imidazole radicals; Pyrazolyl; And triazolyl;
R 2Be O or S;
R 3It is low alkyl group;
R 4Be to be unsubstituted or through halogen atom, cyano group, low alkyl group, lower alkoxy or the pyridine radicals that is unsubstituted or replaces through the piperazinyl that low alkyl group replaces; The pyrimidine radicals that is unsubstituted or replaces through lower alkoxy; The quinolyl that is unsubstituted or replaces through halogen atom; Quinoxalinyl; Or the phenyl that replaces through alkoxyl;
R 5Be hydrogen atom or halogen atom;
N is 0 or 1;
R 6Be oxidation base (oxido);
The condition regulation is if n=1 then has radicals R 6The N atom have positive charge;
R 7Be hydrogen atom or amino;
Or its tautomer, or its medical acceptable salt, or hydrate or solvate,
(b) account at least a nonionic surfactant of about 15 to about 80 weight % amount of said composition, this surfactant is vitamin E-TPGS, and
(c) be selected from least a stripping reinforcing agent of the combination in any of Polyethylene Glycol, poly(ethylene oxide) and above material.
2. medical composition as claimed in claim 1, wherein the chemical compound for the treatment of shown in this formula (I) is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-base-2, the 3-dihydro-imidazol-is [4,5-c] quinoline-1-yl also)-phenyl]-propionitrile or its toluene monooxygenase sulfonate.
3. medical composition as claimed in claim 1, wherein this formula (I) compound or its salt is to exist with about 30 amounts to about 60 weight % based on the gross weight of said composition.
4. medical composition as claimed in claim 1, wherein this at least one nonionic surfactant vitamin E-TPGS is that about 15 amounts to about 45 weight % with said composition exist.
5. medical composition as claimed in claim 1, wherein this at least a stripping reinforcing agent is that about 1 amount to about 15 weight % with said composition exists.
6. medical composition as claimed in claim 1, wherein this at least a stripping reinforcing agent is Polyethylene Glycol.
7. medical composition as claimed in claim 6, wherein this at least a stripping reinforcing agent is PEG3350.
8. medical composition as claimed in claim 1, wherein said composition is mixed with peroral dosage form, preferably is mixed with capsule or medicine bag.
9. medical composition as claimed in claim 1, wherein this medical composition is the supersaturation system.
10. method of making medical composition as claimed in claim 1, its comprise that step (a) merges or hybrid (I) shown in treat chemical compound, said composition about 15 to about 80 weight % amount at least a nonionic surfactant vitamin E-TPGS and be selected from least a stripping reinforcing agent of the combination in any of Polyethylene Glycol (PEG), poly(ethylene oxide) and above material, (b) utilize extruder or other suitable equipment that this mixture is carried out pelletize, simultaneously with this mixture heated to than the low-melting product temperature of this vitamin E-TPGS; And (c) these granules are cooled to room temperature.
11. method of making medical composition as claimed in claim 1, it comprises step: (a) nonionic surfactant vitamin E-TPGS is divided into first and second portion, (b) treat chemical compound shown in merging or hybrid (I), nonionic surfactant vitamin E-the TPGS of this first and be selected from Polyethylene Glycol (PEG), the stripping reinforcing agent of the combination in any of poly(ethylene oxide) and above material, (c) heat this second portion nonionic surfactant vitamin E-TPGS, (d) utilize extruder or other suitable equipment that this mixture is implemented pelletize, simultaneously this second portion nonionic surfactant vitamin E-TPGS slowly is added into this mixture and keeps the product temperature and be lower than about 38 ℃, and (e) these granules are cooled to room temperature.
12. the purposes of a medical composition as claimed in claim 1 in treatment proliferative disease or mTOR kinases dependence disease.
13. the purposes as claim 12, wherein this medical composition is to be enough to provide about 200 to about 70 in object blood plasma, the formula of the AUC of 000ng*h/mL (I) chemical compound or its tautomer, or the amount of its medical acceptable salt or hydrate or solvate gives.
14. medicine box, it comprises (a) medicinal composition for oral use, it comprises granule, these granules comprise at least a nonionic surfactant of the amount of about 15 to the 80 weight % that treat chemical compound, said composition shown in the formula (I), this surfactant is at least a stripping reinforcing agent of vitamin E-TPGS and the combination in any that is selected from Polyethylene Glycol, poly(ethylene oxide) and above material, reach (b) written explanation, wherein these written explanations are pointed out, take between about 2 hours after this medicinal composition for oral use was extremely taken food on the feed in preceding 30 minutes.
15. the purposes of a medical composition as claimed in claim 1 in treatment proliferative disease or mTOR kinases dependence disease, this purposes comprises the object that the medical composition with claim 1 needs with food, cause comparing when not following food to give object with this medical composition, the bioavailability of this formula (I) chemical compound increases when giving described medical composition with food.
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AU2011336478A1 (en) 2013-06-06
GT201300144A (en) 2014-06-09

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